dbSNP rs370155767: GATM:p.Arg23Leu (chr15-45378386-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001482.3(GATM):c.68G>T(p.Arg23Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,367,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

GATM
NM_001482.3 missense, splice_region

Scores

Splicing: ADA: 0.1771

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.89

Publications

0 publications found

Variant links:

Genes affected

GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

GATM Gene-Disease associations (from GenCC):

AGAT deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
Fanconi renotubular syndrome 1
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
primary Fanconi syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22596654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3 link	c.68G>T	p.Arg23Leu	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8 link	c.68G>T	p.Arg23Leu	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000292

AC:

AN:

1367796

Hom.:

Cov.:

AF XY:

0.00000445

AC XY:

AN XY:

674748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29420

American (AMR)

AF:

0.00

AC:

AN:

34230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24482

East Asian (EAS)

AF:

0.00

AC:

AN:

33860

South Asian (SAS)

AF:

0.00

AC:

AN:

77160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4826

European-Non Finnish (NFE)

AF:

0.00000373

AC:

AN:

1072326

Other (OTH)

AF:

0.00

AC:

AN:

57192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;.

PhyloP100

1.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.45

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.28

T;T;D

Sift4G

Benign

0.39

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.28

MutPred

0.41

Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);

MVP

0.32

MPC

0.85

ClinPred

0.98

GERP RS

4.5

PromoterAI

0.057

Neutral

(source)

Varity_R

0.13

gMVP

0.49

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.18

dbscSNV1_RF

Benign

0.35

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over